An international study published in Cell Metabolism, led by Riccardo Bonadonna, the elected president of the Italian Society of Diabetology (SID), is paving the way for a new risk stratification in type 2 diabetes that will allow more intensive and personalized treatment for those at highest risk, before complications arise.
The research would enable immediate deployment of more aggressive therapeutic strategies and tighter monitoring for high-risk individuals, thereby saving years of life and quality of life.
The Study
Publiced in Cell Metabolism, the study involved about 70,000 European-origin individuals with type 2 diabetes, including more than 1,500 newly diagnosed cases. The participants’ complete blood counts (CBC) were analyzed by a specialized algorithm that assigned them to four distinct immune profiles, each associated with a different risk of mortality and complications.
The leukocyte formula (which in a CBC indicates the percentage of circulating immune cells—neutrophils, lymphocytes, monocytes) was interpreted by a special algorithm to identify four distinct, reproducible, and time-stable risk profiles (“endotypes”): a severe inflammatory form (SIND), a mild inflammatory form (MIND), a lymphocyte-rich form (LYRD), and a lymphocyte-deficient form (LYDD).
The higher-risk profiles (SIND and LYDD) are characterized by monocyte-driven inflammation (the immune cells of the innate inflammatory response) and by altered lymphocyte function. In these individuals, the innate immune system is hyperactive, while the adaptive immune system is dysregulated—a double imbalance that over the years can promote vascular and kidney damage observed in the study.
Possible Consequences
People with type 2 diabetes who fall into the SIND and LYDD profiles have a significantly higher risk of cardiovascular events, impaired kidney function, and death compared with the other two groups (LYRD and MIND).
These differences are independent of age, sex, body weight, or HbA1c level: the “endotypes” and the associated risk remain the same even when these factors are controlled, indicating that they reflect an autonomous immunobiology and not merely a more advanced stage of diabetes or a patient who starts off more frail.
Predicting the Risk of Complications
The study opens a new, scalable, low-cost pathway for precision medicine: unlike many molecular classifications that require complex and expensive technologies, the immune endotypes defined in this study are based on the CBC, a low-cost, routine test performed in any analysis lab and already administered at least once to all patients, interpreted by an algorithm already available online.
Incorporating the patient’s immune profile into the assessment of clinical characteristics thus improves the ability to estimate cardiovascular risk compared with the traditional SCORE2-Diabetes score, which is currently used in clinical practice to assess the likelihood of cardiovascular events in people with diabetes.
As Bonadonna explains, this means that from the moment of type 2 diabetes diagnosis—and even years later—it will be possible to identify subgroups of patients at highest risk of complications and premature death, guiding them toward tighter cardiovascular and renal monitoring or toward more aggressive, targeted therapies, well before complications clinically manifest.
The work confirms what the diabetes community has long argued: type 2 diabetes must be addressed by moving beyond traditional classifications based solely on blood glucose and HbA1c to broaden the view to its biological heterogeneity, comments Raffaella Buzzetti, president of the Italian Society of Diabetology.
Study
Vuong B, Delépine C, Ratter-Rieck J …Immunometabolic endotypes define distinct clinical trajectories in type 2 diabetes Cell Metabolism, 2026; 0
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